Typical Anatomy of the Upper Urinary System
The kidneys are organs that have numerous biological roles. Their primary role is to maintain the homeostatic balance of bodily fluids by filtering and secreting metabolites and minerals from the blood and excreting them, along with water, as urine. The ureters are muscular ducts that propel urine from the kidneys to the urinary bladder. In the adult, the ureters are usually 25-30 cm (10-12 inches) long.
The upper urinary system receives autonomic (mostly sympathetic) innervation, by the efferent nervous system. The sensory information is conveyed to the central nervous system (CNS) via the afferent nervous systems. The two systems have different regional distribution; the efferent sympathetic innervation reaches all the segments of the renal vasculature and to a much lesser extent the tubular nephron. The afferent sensory fibers are localized and predominate in the renal pelvis and ureter. The corticomedullary connective tissue contains both types of innervation with a more prominent afferent innervation.
Congestive Heart Failure
Congestive heart failure (CHF) is a very common disorder, affecting 6 million Americans and more than 22 million worldwide. CHF is a disease of the old; it is the leading hospital discharge diagnosis in individuals aged 65 years or older. CHF is the number one reason for hospitalization in people 65 years or older in the United States, accounting for approximately 1 million hospitalizations annually. The cost of hospitalizations for CHF is twice that for all forms of cancer and myocardial infarction combined. Treatment of heart failure costs an estimated $40 billion per year in the United States and nearly $80 billion worldwide.
The Cardio-Renal Syndrome
Renal impairment is an independent and significant predictor of morbidity and mortality in CHF patients. Mortality increases incrementally across the range of renal function, with 7% increased risk for every 10-mL/min decrease in glomerular filtration rate (GFR). CHF triggers kidney dysfunction by a pathological process dubbed the cardio-renal syndrome. The cardio-renal syndrome can be acute, characterized by a rapid decrease in cardiac output together with worsening renal function or chronic, in which gradual worsening of heart and/or kidney function develops over months.
The cardio-renal syndrome is a common condition; in the US, more than 500,000 patients are admitted to hospital every year with acute heart failure, and up 80% of these patients suffer from deteriorating renal functions. High renal sympathetic activity constitutes an important link between CHF and renal dysfunction. Signals of shock and hypoperfusion, present in CHF patients, activate a number of compensation systems to increase the blood pressure and prevent fluid losses. Of these, the renal sympathetic system is one of the most important ones; it effectively reduces renal blood flow and kidney functions, including sodium and water excretion to urine. In addition it activates the renin-angiotensin-aldosterone axis and therefore leads to hypertension, fluid retention and kidney dysfunction. It is now known that increased renal sympathetic drive is an independent factor in terms of progressive deterioration of renal function and adverse outcome in CHF patients as was shown by (Petersson et al., 2005).
The Current Treatment of CHF and the Cardio-Renal Syndrome
As of now, CHF is a progressive, incurable disease. Surgical treatment options are few and are reserved for end-stage patients.
In patients with CHF and volume overload, initial therapy focuses on salt and water restriction and diuretics. Diuretics improve symptoms and quality of life but do not necessarily prolong life. When patients experience persistent pulmonary congestion despite adequate diuretic treatment, they are defined as diuretic resistant. It is unadvised to increase the dose of the diuretic as the potential negative side effects outweigh the possible benefit of fluid removal. One of the most serious side effects of diuretic administration is activation of the renin-angiotensin-aldosterone axis and the sympathetic nervous system that leads to vasoconstriction and hypoperfusion.
Angiotensin-converting enzyme inhibitors (ACEI) and beta blockers are prescribed to most patients for control of hypertension and to reduce cardiac remodeling. Although ACEI and adrenergic blockers are extensively used in these patients, these agents work on a systemic level. As such they cannot be used in an adequate dosage to selectively inhibit the pathological sympathetic renal drive.
Hypertension
Hypertension is one of the most common worldwide diseases afflicting humans. In the US, forty-three million people are estimated to have hypertension, the age-adjusted prevalence of hypertension varying from 18-32%. Because of the associated morbidity and mortality and the cost to society, hypertension is an important public health challenge; hypertension is the most important modifiable risk factor for coronary heart disease (which is the leading cause of death in North America), stroke (the third leading cause), congestive heart failure, end-stage renal disease, and peripheral vascular disease.
Abnormal renal excretory function is one of the most important mechanisms of the initiation and progression of hypertension. Variations of arterial pressure signals the kidney to alter urinary sodium and water excretion. On the long term, maintenance of sodium and water balance by the kidneys is believed to be primary in the long-term control of arterial pressure. Thus, factors that decrease renal excretory function lead to an increase in arterial pressure, which is required to reestablish and maintain sodium and water balance.
The dramatic positive effect of renal denervation on the development of hypertension is evident in a wide variety of animal models in multiple species, suggesting that increased renal nerve activity may be a final common pathway for the defect in renal sodium excretory ability required for the development and maintenance of hypertension.
Chronic Kidney Disease
Chronic kidney disease (CKD) is a major cause of morbidity and mortality, particularly at the later stages. More than 400,000 patients (US) are on dialysis per year at an annual cost up to $67,000 for each patient. The 5-year survival rate for a patient undergoing chronic dialysis in the United States is approximately 35%. The most common cause of death in the dialysis population is cardiovascular disease.
A large body of evidence indicates the presence of functional abnormalities of the sympathetic nervous system in uremic animals and humans. In patients with bilateral nephrectomy, the rate of sympathetic discharge was lower than in patients with their native kidneys, and this increased rate was accompanied by lower mean arterial pressure and regional vascular resistance.
Sympathetic activation contributes to progressive kidney damage by elevation of blood pressure and by promoting atherosclerosis. Increased sympathetic activity, progressive atherosclerosis and elevated blood pressure contribute to the development of cardiac remodeling and functional alterations. These conditions are highly prevalent in patients with CKD.
Current treatment aims for CKD are to halt the progression of the renal damage by controlling the underlying condition that triggers the damage, i.e. hypertension and diabetes. Prescription of ACEI in such patients should take into account the potential influence of renal impairment on ACEI metabolism, and adverse effects on the renal function itself (especially hypotension and acute reductions in glomerular filtration rate which if untreated can escalate to acute renal failure).
Drugs that act on the sympathetic overactivity, such as alpha and beta adrenergic blockers are second or third line of treatment. These agents have significant side effects; alpha blockers were recently shown to increase the risk for stroke in patients with essential hypertension. Beta blockers are associated with intradyalitic hypotension.
As GFR decreases, diuretics are increasingly required for excretion of the daily water load. However, for a number of reasons diuretics become relatively ineffective in patients with a moderate to severe degree of chronic kidney disease (creatinine clearance below approximately 35 ml·min-1). Diuretics can lead to further rise in the serum creatinine and blood urea nitrogen concentrations and a high incidence of hypokalemia and electrolyte disorders. Furthermore, net losses of sodium and fluid during regular diuretic administration are limited by postdiuretic renal sodium and fluid retention. Because of these complications, diuretic use in the final stages of chronic kidney disease, although desirable theoretically to maintain body water balance is impractical because of the severe side effects
Acute Renal Failure
Causes of acute renal failure (ARF) can be broadly divided into three clinical categories: a) Prerenal, which is an adaptive response to severe volume depletion b) renal (or intrinsic), in response to kidney insult, including contrast material and c) postrenal.
Prerenal ARF is the most common cause of ARF. It often leads to intrinsic ARF if it is not promptly corrected. Acute reduction of renal blood flow (RBF), either because of blood loss or hypotension can result in this syndrome. The hallmark of intrinsic ARF and the most common form is acute tubular injury (ATN). Prerenal ARF and ATN occur on a continuum of the same pathophysiological process and together account for 75% of the cases of ARF.
It cannot be overstated that the current treatment of ARF is mainly supportive in nature and no therapeutic modalities to date have shown efficacy in treating the condition. Indications of immediate dialysis treatment include hyperkalemia not responsive to conventional treatment, pulmonary edema, and uremia.
Mortality rate estimates in ARF patients vary from 25-90%. The in-hospital mortality rate is 40-50%; in intensive care settings, the rate is 70-80%. The mortality in patients requiring dialysis is about 50%. Mortality rates have changed little over the last two decades, reflecting the fact that there is no adequate treatment for this condition.
The following patents and publication may relate to stimulation of the urinary system. Their disclosures are incorporated herein by reference. Some embodiments of the invention use apparatus described therein and/or processes and/or physiological effects described therein, with the appropriate changes, and/or in combination with methods and/or apparatus described herein, to provide functionality in accordance with some embodiments of the invention.
US Patent Application Publications:
2005/0228459, 2005/0228460, 2005/0234523, 2005/0288730, 2006/0025821, 2006/0041277, 2006/0116720, 2006/0142801, 2006/0206150, 2006/0212076, 2006/0212078, 2006/0235474, 2006/0265014, 2006/0265015, 2006/0271111, 2006/0276852, 2007/0066957, 2007/0083239, 2007/0112327, 2007/0129760, 2007/0129761, 2007/0135875, 2007/0173899, 2007/0203549, 2007/0208382, 2007/0265687, 2007/0282184, 2008/0119907, 2008/0213331, 2008/0255642, 2009/0024195, 2009/0036948, 2009/0062873, 2009/0076409 and 2009/0221939.
US Patents:
U.S. Pat. Nos. 5,749,845, 6,425,877, 6,500,158, 6,692,490, 6,699,216, 6,743,197, 6,978,174, 7,162,303, 7,326,235, 7,617,005 and 7,620,451.
Non-US Patents and Publications:
RU 2004103992/14, RU 2271840 C2, WO 97/44088 and WO 2004/075948.
Other Publications
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